Maternal LSD1/KDM1A is an essential regulator of chromatin and transcription landscapes during zygotic genome activation

How the parental genomes of the very specialized sperm and oocyte cells are remodelled upon fertilization to confer totipotency has remained a tantalizing open questions. Indeed, in the case of mammals, the parental genomes undergo dramatic reprogramming upon fertilization, including differential dynamics of histone post-translational modifications. The roles of histone modifying enzymes in this process, which are maternally provided, are only just starting to emerge. Here, we explore the function of the oocyte inherited pool of Lsd1/Kdm1a, which encodes a histone H3K4 and K9 demethylase, during early mouse development. Maternal deficiency of Lsd1/Kdm1a results in developmental arrest by the two-cell stage, associated with dramatic and stepwise alterations in H3K9 and H3K4 methylation patterns depending on its demethylase activity. At the transcriptional level, two major changes occur. On one hand, switch from maternal-to-zygotic program fails to be induced. On the other hand, LINE-1 retrotransposons are not properly silenced, along with evidences for increased LINE-1 activity. We propose that Lsd1/Kdm1a is involved in the correct establishment of epigenetic information harboured by histones and is involved in the initiation of new pattern of genome expression driving early mouse development and preserving genome integrity RNA-seq of individual mouse two-cell stage embryos高度特化的精子与卵母细胞的亲本基因组，在受精后如何发生重编程以赋予细胞全能性，始终是一个引人入胜的未解难题。事实上，对于哺乳动物而言，亲本基因组在受精后会经历剧烈的重编程过程，其中包括组蛋白翻译后修饰的差异化动态变化。而母源供给的组蛋白修饰酶在此过程中所发挥的作用，直至近年才逐渐被学界所认知。本研究探讨了卵母细胞遗传所得的Lsd1/Kdm1a基因——其编码组蛋白H3K4与H3K9去甲基化酶——在小鼠早期发育过程中的功能。母源Lsd1/Kdm1a缺失会导致胚胎发育停滞于二细胞阶段，该表型与H3K9和H3K4甲基化模式的剧烈、渐进式改变密切相关，且该改变依赖于其去甲基化酶活性。在转录层面，存在两项主要变化：其一，母源向合子的转录程序转换无法被成功诱导；其二，LINE-1逆转录转座子未能被正常沉默，同时伴随LINE-1活性升高的相关实验证据。我们提出，Lsd1/Kdm1a参与组蛋白所承载的表观遗传信息的正确建立，并参与启动驱动小鼠早期发育、维持基因组完整性的全新基因组表达程序；本研究同时附带了单个小鼠二细胞胚胎的RNA测序（RNA-seq）数据集。